Kaska Koltowska's research projects

Understanding lymphatic specification

During lymphatic development lymphatic progenitors are marked by onset of expression of transcription factor, Prox1. My work has delved into the earliest stages of lymphatic endothelial cell (LEC) specification from venous endothelial cells (VECs) and took on the challenge of dissecting how lymphatic cells become specified by investigating zebrafish lymphatic development in real time in vivo.

This work resulted in the discovery of unexpected cellular behaviours during lymphatic specification. We uncovered that both cell division and molecular signals are crucial for lymphatic cell identity. We observed that the induction of Prox1 is a progressive process. This is coupled with bipotential LEC progenitors undergoing a cell division prior to sprouting from the cardinal vein (CV). After cell division, one daughter cell progressively increases levels of Prox1 and becomes a LEC. The other remains behind, loses Prox1 expression and becomes a VEC. In this project we have also found that Vegfc signalling is apical to this process and drives cell division and Prox1 expression in lymphatic daughter cells.

This work posed a further question, that we are currently investigating, of how Vegfc signalling and Prox1 transcriptional cascade together coordinate the molecular inputs to drive the cell division and refine lymphatic fate.

Reference: Koltowska K#, Lagendijk AK#, Pichol-Thievend C, Fischer JC, Francois MF, Ober EA, Yap AS, Hogan BM. Vegfc regulates bipotential precursor division and Prox1 expression to promote lymphatic identity in zebrafish. Cell Rep. 2015 Dec 1;13(9):1828-41. # equal contribution

Transcriptional control of lymphangiogenesis

During lymphatic development, Vegfc signalling and Prox1 are key in establishing lymphatic identity, sprouting and proliferation. Once lymphatic endothelial cells leave the cardinal vein, they undergo cellular rearrangements and migrate to form the vascular network.

In this project, using forward genetics in zebrafish we identified the transcription factor gene mafba as essential for lymphatic vessel development. We found that mafba is required cell autonomously for the migration of lymphatic precursors after their initial sprouting from the posterior cardinal vein. Mechanistically, Vegfc-signalling increases mafba expression to control downstream transcription and this is dependent on the activity of SoxF transcription factors.

We are currently investigating the molecular hierarchy of the mafba transcriptional cascade.

References:

Arnold H., Panara V, Hußmann M., Filipek-Gorniok B., Skoczylas R., Ranefall P., Gloger M., Allalou A., Hogan B., Schulte-Merker S., Koltowska K. Mafba and Mafbb Differentially Regulate Lymphatic Endothelial Cell Migration in Topographically Distinct Manners. Cell Rep. 2022 Jun 21;39(12):110982. PMID: 35732122

Koltowska K, Paterson S, Bower NI, Baillie GJ, Lagendijk AK, Astin JW, Chen H, Francois M, Crosier PS, Taft RJ, Simons C, Smith KA, Hogan BM. mafba is a downstream transcriptional effector of Vegfc signalling essential for embryonic lymphangiogenesis in zebrafish. Genes Dev. 2015 Aug 1;29(15):1618-30.